NLRP3 inflammasome driven liver injury and fibrosis: roles of IL-17 and TNF in mice
Open accessAbstract
The NLRP3 inflammasome, a caspase‐1 activation platform, plays a key role in the modulation of liver inflammation and fibrosis. Here, we tested the hypothesis that interleukin 17 (IL‐17) and tumor necrosis factor (TNF) are key cytokines involved in amplifying and perpetuating the liver damage and fibrosis resulting from NLRP3 activation. To address this hypothesis, gain‐of‐function Nlrp3 A350V knock‐in mice were bred onto il17a and Tnf knockout backgrounds allowing for constitutive Nlrp3 activation in myeloid derived cells in mice deficient in IL‐17 or TNF. Livers of Nlrp3 A350V knock‐in mice exhibited severe liver inflammatory changes characterized by infiltration with neutrophils, increased expression of chemokine (C‐X‐C motif) ligand (CXCL) 1 and CXCL2 chemokines, activated inflammatory macrophages, and elevated levels of IL‐17 and TNF. Mutants with ablation of il17a signal showed fewer neutrophils when compared to intact Nlrp3 A350V mutants, but still significant inflammatory changes when compared to the nonmutant il17a knockout littermates. The severe inflammatory changes associated with mutant Nlrp3 were almost completely rescued by Tnf knockout in association with a marked decrease in circulating IL‐1β levels. Intact Nlrp3 A350V mutants showed changes in liver fibrosis, as evidenced by morphometric quantitation of Sirius Red staining and increased mRNA levels of profibrotic genes, including connective tissue growth factor and tissue inhibitor of matrix metalloproteinase 1. Il17a lacking mutants exhibited amelioration of the aforementioned fibrosis, whereas Tnf ‐deficient mutants showed no signs of fibrosis when compared to littermate controls. Conclusion : Our study uncovers key roles for TNF and, to a lesser extent, IL‐17 as mediators of liver inflammation and fibrosis induced by constitutive NLRP3 inflammasome activation in myeloid‐derived cells. These findings may lead to therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis in various liver pathogeneses driven by NLRP3 activation. (H epatology 2018;67:736‐749).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In advanced liver fibrosis, macrophages maintain the inflammatory environment and accelerate liver fibrosis deterioration by secreting proinflammatory cytokines.
“In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines.”
From An Autologous Macrophage‐Based Phenotypic Transformation‐Collagen Degradation System Treating Advanced Liver Fibrosis (2024) · cites this paper as [13]
The Introduction and Results (page numbers unavailable) link activated macrophages and inflammatory cytokines to liver inflammation, and associate inflammatory macrophage infiltration with fibrosis in NLRP3-mutant mice. The paper does not establish that macrophages secrete the cytokines responsible for worsening fibrosis specifically at an advanced stage; its findings concern inflammation and fibrosis development in mice. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIncreased abundance of these inflammatory cytokines maintains the liver inflammatory environment and accelerates subsequent progression of liver fibrosis.
“The increased abundance of these inflammatory cytokines maintain the liver inflammatory environment and accelerate the subsequent progression of LF.[ 13 ]”
From An Autologous Macrophage‐Based Phenotypic Transformation‐Collagen Degradation System Treating Advanced Liver Fibrosis (2024) · cites this paper as [13]
The Discussion (page unavailable) reports increased TNF and IL-17 in the livers of Nlrp3-mutant mice, but says TNF—not IL-17—was crucial for liver inflammation and fibrogenic pathways. The Results (page unavailable) found that removing TNF prevented increased collagen deposition, whereas removing IL-17 did not. The claim overstates the shared role of both cytokines and extends a mouse-model finding to liver fibrosis generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCaspase 1, NOD receptors, LRR receptors, the NLRP3 pathway and NF-κB have all been identified as upstream activators of the IL-17A-TGFβ axis.
“These include caspase 1, NOD receptors, LRR (leucine-rich repeats) receptors, the NLRP3 pathway and NF-κB, which have all been identified as upstream activators of the IL-17A–TGFβ axis.104”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [104]
Alarmin cytokines TSLP, IL-25, and IL-33 initiate type 2-dependent fibrosis by triggering production of IL-4 and IL-13 in innate lymphoid cells, T cells, eosinophils, and other type 2-associated leukocytes.
“the alarmin cytokines thymic stromal lymphopoietin, IL-25, and IL-33 function as key initiators of type 2-dependent fibrosis by triggering the production of IL-4 and IL-13 in innate lymphoid cells, T cells, eosinophils, and other type 2-associated leukocytes129–132”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [131]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 51 · Cited by 266
- Authors
- Wree, A., McGeough, M. D., Inzaugarat, M. E., Eguchi, A., Schuster, S., Johnson, C. D., Peña, C. A., Geisler, L. J., Papouchado, B. G., Hoffman, H. M., & Feldstein, A. E.
- Affiliations
- University of California San Diego (US)
- Department of Internal Medicine III,RWTH University Hospital Aachen,Germany
- Universitätsklinikum Aachen (DE)
- Corresponding author
- Feldstein, Ariel E.
- ORCID
- Venue
- Hepatology
- Published
- 2017-12-28
- Volume
- 67
- Issue
- 2
- Pages
- 736-749
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC5849484
- OpenAlex
- W2756425706
- Cited by
- 266
- References
- 51
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 36 · 2023: 44 · 2022: 46 · 2021: 36 · 2020: 32 · 2019: 19 · 2018: 13 · 2017: 3
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB‐TRR57, WR173/2‐1, WR173/2-1 and SFB/TRR 57)
- RWTH Aachen University
- Swedish Orphan Biovitrum
- National Institutes of Health (AI52430, DK082451)
- University of California, San Diego (#NS047101, P30 NS047101)
- National Institute on Alcohol Abuse and Alcoholism (U01AA024206)
- National Institute of Allergy and Infectious Diseases (R01AI052430)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082451, R01DK076852, R01DK113592)
- National Institute of Neurological Disorders and Stroke (P30NS047101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- NLRP3 inflammasome, liver fibrosis, liver injury, IL-17, TNF-α, caspase-1, myeloid-derived cells, neutrophil infiltration, CXCL1, CXCL2, IL-1β, connective tissue growth factor, tissue inhibitor of matrix metalloproteinase-1, inflammatory macrophages
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Hepatitis, Liver Cirrhosis, Experimental, Macrophages, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-17, Neutrophil Infiltration, Mice, Hepatic Stellate Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
